Fluid transport and distribution manifold

ABSTRACT

A structured assembly of perpendicular, interwoven fluidic conduits permits connections between conduits to be readily (and in some cases visibly) established, thereby providing operational convenience and amenability to automated means of validation or verification.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to and the benefit of, and incorporatesherein by reference in its entirety, U.S. Ser. No. 63/075,447, filed onSep. 8, 2020, the entire disclosure of which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates, generally, to fluid transport anddistribution in biological production processes.

BACKGROUND

Biopharmaceuticals and vaccines are commonly produced or manufacturedusing a series of operations intended to express, recover, and stabilizeproteins or other pharmaceutical ingredients as part of a manufacturingprocess. These operations involve the delivery, transfer and disposal ofone or more fluid media and buffers comprising combinations of salts,chemicals, and other substances intended to support specific steps inthe production process. Examples of such operations include cellcultivation or fermentation, buffer exchange, chromatography,concentration, precipitation, and crystallization. Forbiopharmaceuticals and vaccines, the assurance of aseptic transfer andprocessing is also important.

Common means of storing and transferring these fluids in a singleoperation or in multiple operations involve conduits or pipes to deliverthe fluids from one location, such as a storage tank, to another. Theseconduits for transfer can be made of stainless steel or other similarinert metals that can be cleaned to remove residual materials by anumber of methods including exposure to steam, chemicals, heat, orcombinations. Any single operation among the plurality of steps requiredfor manufacturing can require transfer of different fluids to achievethe completion of the process. For chromatographic operations usingresins to recover pharmaceutical ingredients or to remove impuritiesfrom the fluids, the number of buffers used may range from 4 to 10fluids. A typical manufacturing process may include 3-6 or more steps ofthis type. In total, the unique number of fluid-carrying conduits canrange from two to 20 to 100 or more. Similarly, a multiplicity ofbuffers or fluids may be used for non-chromatographic separationoperations such as tangential flow filtration, ultrafiltration,diafiltration, membrane separations or other filter methods common inthe industry.

Disposable fluidic conduits can reduce the chemical waste required forcleaning fixed conduits between operations, improve the assurance ofaseptic operations, and reduce the time required to build newmanufacturing sites or processes for new pharmaceutical ingredients.These disposable fluidic conduits often comprise biocompatible materialssuch as silicone tubing or other plastics. The conduits often arecustomized in length and terminal connections to connect differentequipment in the process. The connections may include direct connectionsto other disposable components such as bags or containers or adaptableconnectors designed to allow aseptic connection to another conduit. Inthis way, a set of assembled conduits can be connected to allow for theconnectivity of the plurality of fluids and transfers required for oneor more operations of bioprocessing.

The components needed for a particular application may include tubes,connectors, bags, valves and the like, and these basic elements may beassembled into complex fluid-transfer systems as needed to effect thevarious operational stages of the application. Because the componentstend to be so simple and versatile, the assembled systems can becomeungainly and difficult to reproduce. An operator may be required tofollow detailed instructions to assemble a kit of basic parts into acomplex functional apparatus. Errors in connecting the components orsub-assemblies of components can degrade operation and render the systemunusable for drug manufacturing or other production lines requiring highlevels of assurance. Hence, there is a need for flexible, scalable,intermediate-level fluid-transfer components that are versatile enoughto serve in a broad range of deployments, and which will also helpreduce or minimize operator error.

SUMMARY

Embodiments of the present invention utilize a structured assembly offluidic conduits that permits connections between conduits to be readily(and in some cases visibly) established, thereby providing operationalconvenience and amenability to automated means of validation orverification.

Accordingly, in a first aspect, the invention relates to fluid transportand distribution manifold comprising, in various embodiments, a support;a first plurality of parallel fluid conduits passing through thesupport; and a second plurality of parallel fluid conduits passingthrough the support perpendicular to, and interwoven with, the firstfluid conduits; at least some of the second fluid conduits areselectably fluidly connected to one or more of the first plurality offluid conduits. The first and second conduits may be interlaced as warpand weft.

In various embodiments, the manifold further comprises a multiport valvehead, and the first plurality of parallel fluid conduits terminate atthe valve head. Fluid connections between the first and second fluidconduits may be established by permanent connections therebetween or byadjustable transfer valves. The transfer valves, which may be checkvalves, can be manually or electronically adjustable. For example, themanifold may further comprise circuitry for receiving user commands and,in response thereto, electronically adjusting at least one of thetransfer valves. Such circuitry may comprise a wired and/or wirelessnetwork interface for receiving the user commands, e.g., specifying atransfer valve and an opening level thereof.

In various embodiments, each of the first conduits is connected, viaseparate transfer valves, to all of the second conduits. The support mayinclude a rigid frame for retaining the first and second conduits in theperpendicular, interwoven configuration. For example, the support mayinclude channels of differing depths for receiving the conduits andenforcing the perpendicular, interwoven configuration. In someembodiments the manifold includes, integral with the support, a firstplurality of connectable ports each affording fluid access to a free endof one of the first conduits. The may include, integral with thesupport, second and third pluralities of connectable ports, each of thesecond connectable ports affording fluid access to a first end of one ofthe second conduits and each of the third connectable ports affordingfluid access to a second end of one of the second conduits.

In another aspect, the invention pertains to a method of fluid transportcomprising, in various embodiments, the steps of interweaving first andsecond pluralities of parallel fluid conduits, the first and secondpluralities of fluid conduits being substantially perpendicular to eachother; fluidly connecting each of at least some of the second fluidconduits to one or more of the first plurality of fluid conduits; andcausing fluid to flow from at least some of the first fluid conduitsinto second fluid conduits to which they are fluidly connected. Thefluid connections may be permanent or adjustable and valved.

As used herein, the term “approximately” means±10%, and in someembodiments, ±5%. Reference throughout this specification to “oneexample,” “an example,” “one embodiment,” or “an embodiment” means thata particular feature, structure, or characteristic described inconnection with the example is included in at least one example of thepresent technology. Thus, the occurrences of the phrases “in oneexample,” “in an example,” “one embodiment,” or “an embodiment” invarious places throughout this specification are not necessarily allreferring to the same example. Furthermore, the particular features,structures, routines, steps, or characteristics may be combined in anysuitable manner in one or more examples of the technology. The headingsprovided herein are for convenience only and are not intended to limitor interpret the scope or meaning of the claimed technology.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and the following detailed description will be morereadily understood when taken in conjunction with the drawings, inwhich:

FIG. 1A is a perspective, partially transparent view of a distributionmanifold in accordance with embodiments of the invention,

FIG. 1B is an enlarged view of the rotary valve shown in FIG. 1A, andincluding the fluidic connections made for operation.

FIG. 2 is another enlarged view of the rotary e shown in FIGS. 1A and1B, with additional mechanical features indicated.

FIG. 3 schematically illustrates a programmable version of thedistribution manifold shown in FIG. 1A.

DETAILED DESCRIPTION

Refer first to FIGS. 1A and 1B, which illustrate a representative fluidtransport and distribution manifold 100. The manifold 100 includes asupport 110, a first plurality of (vertical) parallel fluid conduitsrepresentatively indicated at 120 that terminate at a multiport valvehead 125. The support 110 includes a backplate 130, a raised platform135, and a cover plate 140 that protects the fluid conduits but leavesthe valve head 125 exposed and accessible. The cover plate 140 may besecured to the raised platform 135 by screws (as illustrated),heat-sealing, glue or other means of fastening, and may be transparentto allow for leak detection and verification of proper assembly. Theterminal portions of the fluid conduits 120 seat within recessedchannels 145 and pass under the edge of the cover plate 140, eachextending in a loop to connect to a port of the valve head 125. Therotary valve head 125 facilitates selectable fluid connection between anoutlet or inlet line 155 and one of the fluid conduits 120. As shown inFIG. 2 , the cover plate 140 may include identifiers (e.g., numbers,letters or machine-readable markings) specifying the position on therotary valve head 125 to which the indicated conduit 120 corresponds. Asshown in FIG. 2 , the front face of the rotary valve head 125 is rotateduntil the desired conduit is brought into the home position, fluidicallyconnecting it to the line 155. The looped terminal portions of theconduits 120 extend to accommodate this rotation without stress.Optionally, a locking lever 157 may be coupled to a Belleville springstack 158 to rotationally lock the rotary valve head 125 in a selectedposition. A pair of lever stops 159 ensure finger clearance.

A second plurality of (horizontal) parallel fluid conduits 160 passesthrough the support 110 perpendicular to, and interwoven with, the firstfluid conduits 120. Interweaving can take various forms. In FIG. 1A,successive conduits 140 pass behind and in front of the conduits 120 inan alternating fashion. This is achieved by seating the conduits 160 inchannels having alternating deep (e.g., conduit 160) and shallow (e.g.,conduit 160 s) depths. The channels 145 through which the fluid conduits120 pass have an intermediate depth. In this configuration, half of thefluid conduits 160 lie above the perpendicular conduits 120 and half liebelow. Alternatively, the conduits 120 may form a warp and the conduits160 may be individually woven (i.e., interlaced) therethrough in a weft,or the conduits 160 may form a warp and the conduits 120 may beindividually woven therethrough in a weft—i.e., an x-y weave. Moreelaborate “stitching” patterns” are possible, e.g., a set of two weavesinterlaced and rotated 90° relative to one another (i.e., additionallines on the diagonals).

Connections may be made as desired between vertical and horizontalconduits; each horizontal conduit may be connected to one or morevertical conduits, or to no other conduits, and similarly, each verticalconduit may be connected to one or more horizontal conduits, or to noother conduits. For example, the horizontal conduits 160 may delivervarious analytical reagents and the vertical conduits 120 may deliversamples to be tested. Each sample may require mixing with one ormultiple reagents delivered via individual conduits 140. A conduit mayor may not terminate at its connection with another conduit.

Fluidic connections between vertical and horizontal conduits may bepermanent, temporary, or programmable. The interwoven arrangement ofconduits affords room for adjacent connections to be established withoutcrowding or interference. In some embodiments, connections are made bypermanent connectors that, for example, pierce both conduits andestablish fluid-tight connections between them. Alternatively, as shownin FIG. 1A, connections may be made using T-connectors 170, whichterminate the associated vertical conduit 120 and create a fluid path tothe lumen of a horizontal conduit 160. These connectors may be installedin any desired number and configuration, and may include check valvesthat, for example, permit entry of reagent into a sample-containingconduit but prevent reverse travel of sample into the reagent conduit(which may supply other sample conduits).

In some embodiments, the connections are established by adjustabletransfer valves. For example, in the system 300 shown in FIG. 3 , atransfer valve 310 is placed at some or all conduit intersections andmay be selectively activated, by a controller 320, to achieve a desiredpattern of connections. In particular, these valves 310 may be manuallyand/or electrically adjustable by the controller 320, allowing thetransfer rate to be selectable from no flow at all to a maximum flowbetween conduits. In one implementation, the valves are electricallyactuable and the pattern of desired valve actuation states iscommunicated to the controller 320 and stored in an associatednonvolatile (e.g., Flash) memory 325. For example, the controller mayhave a conventional wireless (or wired) interface 330 and receivecommands from a user via, for example, a phone or tablet. Thesecommands, entered via an interface or communicated as a graphicalpattern, dictate the state (i.e., the degree of opening) of eachcontrolled valve 310. The controller sends signals to the valves 310 toplace them electromechanically in the programmed state, which ispersistent. The valves 310 may include flow sensors whose outputs areperiodically sensed by the controller 320 to set the valve initially andthereafter ensure conformance with the stored actuation pattern; anydetected deviation may be corrected by appropriate control signals sentto the deviant valve. The controller 320 and memory 325 may be located,for example, between the backplate 130 and the raised platform 135.Suitable electromechanically actuable valves are conventional andreadily available.

The fluid conduits 120 terminate at the valve head 130, as shown. Theopposite ends of some or all of the conduits 120 may also terminate atthe edge of the manifold 100, e.g., in luer locks or similar fittingsallowing fluid-tight connections to be established. Some or all of thefluid conduits 160 may similarly terminate, at one or both ends, at theedge of the manifold 100. It should be noted that the valve head 125 isoptional. In some embodiments, the outlets of all of the fluid conduits120 exit the manifold 100, i.e., a single conduit 120 is not selected.The manifold acts to establish selectable connections among theintersecting conduits.

The manifold 100 may include features allowing attachment to anothercomponent used in manufacturing. These features may include holes,hangers, velcro, or other attachment elements. In some embodiments, themanifold 100 can mount onto a custom holding element on a receivingcomponent for mounting. In some cases, this feature includes aconventional locking mechanism to hold the array in place afterattachment. In some cases, this element is connected to an electrical ormechanical sensor.

In embodiments where connections among conduits are made manually, thepattern of connections is desirably visible through the cover plate 140and may be recorded by a digital camera, scanner, video recording deviceor other means of capturing images and interpreted by a computer visionor other recognition system to categorize the manifold 100 among aplurality of possible types, each, for example, corresponding to aparticular application. This simplifies manufacture and distribution,and also allows for verification when a manifold is installed inproduction. The sensed pattern may be communicated to the controller 320of a programmable embodiment 300 to replicate the pattern.

Alternatively or in addition, markings may be placed on the manifold 100to indicate the orientation of the structured array for installation or,once again, to assure the identity of the assembly. In some instances,the manifold 100 also includes (or may receive) a RFID or other passivesignaling device. In some instances, the manifold 100 is marked with abarcode. In some embodiments, the shape of the manifold and surroundingsupport 110 is associated with the number and placement of conduits.

The controller 320 may be implemented in hardware, software or acombination of the two. For embodiments in which the functions areprovided as one or more software programs, the programs may be writtenin any of a number of high level languages such as PYTHON, PASCAL, JAVA,C, C++, C#, BASIC, various scripting languages, and/or HTML.Additionally, the software can be implemented in an assembly languagedirected to the microprocessor resident on a target computer; forexample, the software may be implemented in Intel 80x86 assemblylanguage. The software may be embodied on an article of manufactureincluding, but not limited to, a PROM, an EPROM, EEPROM, orfield-programmable gate array (FPGA). Embodiments using hardwarecircuitry may be implemented using, for example, one or more FPGA, CPLDor ASIC processors, or a conventional microprocessor or microcontroller.

The terms and expressions employed herein are used as terms andexpressions of description and not of limitation, and there is nointention, in the use of such terms and expressions, of excluding anyequivalents of the features shown and described or portions thereof. Inaddition, having described certain embodiments of the invention, it willbe apparent to those of ordinary skill in the art that other embodimentsincorporating the concepts disclosed herein may be used withoutdeparting from the spirit and scope of the invention. Accordingly, thedescribed embodiments are to be considered in all respects as onlyillustrative and not restrictive.

What is claimed is:
 1. A fluid transport and distribution manifoldcomprising: a support; a first plurality of parallel fluid conduitspassing through the support; a second plurality of parallel fluidconduits passing through the support perpendicular to, and interwovenwith, the first plurality of parallel fluid conduits, at least some ofthe second plurality of parallel fluid conduits being selectably fluidlyconnected to one or more of the first plurality of parallel fluidconduits; and a multiport valve head, the first plurality of parallelfluid conduits terminating at the valve head.
 2. The manifold of claim1, wherein fluid connections between fluid conduits in the first andsecond pluralities of parallel fluid conduits are established bypermanent connections therebetween.
 3. The manifold of claim 1, whereinfluid connections between fluid conduits in the first and secondpluralities of parallel fluid conduits are established by adjustabletransfer valves.
 4. The manifold of claim 3, wherein the transfer valvesare manually adjustable.
 5. A fluid transport and distribution manifoldcomprising: a support; a first plurality of parallel fluid conduitspassing through the support; and a second plurality of parallel fluidconduits passing through the support perpendicular to, and interwovenwith, the first plurality of parallel fluid conduits, at least some ofthe second plurality of parallel fluid conduits being selectably fluidlyconnected to one or more of the first plurality of parallel fluidconduits, wherein fluid connections between fluid conduits in the firstand second pluralities of parallel fluid conduits are established byadjustable transfer valves, and wherein the transfer valves are checkvalves.
 6. The manifold of claim 3, wherein the transfer valves areelectronically adjustable and further comprising circuitry for receivinguser commands and, in response thereto, electronically adjusting atleast one of the transfer valves.
 7. The manifold of claim 6, whereinthe circuitry comprises a network interface for receiving the usercommands.
 8. The manifold of claim 7, wherein the network interface iswired.
 9. The manifold of claim 7, wherein the network interface iswireless.
 10. The manifold of claim 6, wherein the user commands eachspecify a transfer valve and an opening level thereof.
 11. The manifoldof claim 3, wherein each of the first plurality of parallel fluidconduits is connected, via separate transfer valves, to all of thesecond plurality of parallel fluid conduits.
 12. The manifold of claim1, wherein the support includes channels of differing depths forreceiving the first and second pluralities of parallel fluid conduitsand enforcing the perpendicular, interwoven configuration.
 13. A fluidtransport and distribution manifold comprising: a support; a firstplurality of parallel fluid conduits passing through the support; and asecond plurality of parallel fluid conduits passing through the supportperpendicular to, and interwoven with, the first plurality of parallelfluid conduits, at least some of the second plurality of parallel fluidconduits being selectably fluidly connected to one or more of the firstplurality of parallel fluid conduits, wherein the support comprises arigid frame for retaining the first and second conduits in theperpendicular, interwoven configuration.
 14. The manifold of claim 13,wherein the support includes channels of differing depths for receivingthe first and second pluralities of parallel fluid conduits andenforcing the perpendicular, interwoven configuration.
 15. A fluidtransport and distribution manifold comprising: a support; a firstplurality of parallel fluid conduits passing through the support; asecond plurality of parallel fluid conduits passing through the supportperpendicular to, and interwoven with, the first plurality of parallelfluid conduits, at least some of the second plurality of parallel fluidconduits being selectably fluidly connected to one or more of the firstplurality of parallel fluid conduits; and integral with the support, afirst plurality of connectable ports, each of the first connectableports affording fluid access to a free end of one of the first pluralityof parallel fluid conduits.
 16. A fluid transport and distributionmanifold comprising: a support; a first plurality of parallel fluidconduits passing through the support; a second plurality of parallelfluid conduits passing through the support perpendicular to, andinterwoven with, the first plurality of parallel fluid conduits, atleast some of the second plurality of parallel fluid conduits beingselectably fluidly connected to one or more of the first plurality ofparallel fluid conduits; and integral with the support, second and thirdpluralities of connectable ports, each of the second connectable portsaffording fluid access to a first end of one of the second plurality ofparallel fluid conduits and each of the third connectable portsaffording fluid access to a second end of one of the second plurality ofparallel fluid conduits.
 17. A fluid transport and distribution manifoldcomprising: a support; a first plurality of parallel fluid conduitspassing through the support; and a second plurality of parallel fluidconduits passing through the support perpendicular to, and interwovenwith, the first plurality of parallel fluid conduits, at least some ofthe second plurality of parallel fluid conduits being selectably fluidlyconnected to one or more of the first plurality of parallel fluidconduits, wherein fluid conduits in the first and second pluralities ofparallel fluid conduits are interlaced as warp and weft.
 18. A method offluid transport comprising the steps of: interweaving first and secondpluralities of parallel fluid conduits, the first and second pluralitiesof parallel fluid conduits being substantially perpendicular to eachother, wherein the first and second pluralities of parallel fluidconduits are retained by a rigid frame of a support in theperpendicular, interwoven configuration, and/or the first plurality ofparallel fluid conduits terminates at a multiport valve head; fluidlyconnecting each of at least some of the second plurality of parallelfluid conduits to one or more of the first plurality of parallel fluidconduits; and causing fluid to flow from at least some of the firstplurality of parallel fluid conduits into at least some of the secondplurality of parallel fluid conduits to which they are fluidlyconnected.
 19. The method of claim 18, wherein the fluid connections arepermanent.
 20. The method of claim 18, wherein the fluid connections areadjustable and valved.